Laboratory instrumentation used in medicine and other chemically related industries has reached a high level of sophistication in recent years. For example, clinical laboratory instrumentation can now process hundreds of samples routinely in a day in batch modes, multiply and sequentially at a high sample rate, or selectively with specific test sets. Clinical laboratory methods of analysis fulfill much of the need for routine diagnosis; however, many clinical situations arise wherein the concentration of some chemical species change so rapidly that infrequent, intermittent measurements give the clinician a distorted evaluation of the patient status. In addition, this type of retrospective analysis does not reveal trends that might be considered significant and even dangerous.
Off-line or in vitro monitoring methods and apparati presently used are not capable of providing continuous measurement as they suffer from time-consuming laboratory analysis and other distinct disadvantages. For example, in animal or human medicine in vitro diagnostic instruments housing one or more sensing elements capable of measuring one or more selected substances in blood, urine and other body fluids have significant time lags (typically 20 minutes to one hour) between the time of sample withdrawal from the patient to when the sample is analyzed and the results made available. Thus, there is no instantaneous feedback or indications of trends which would allow the clinician better control over the administration of therapeutic agents and continually monitor their effects. In addition, repeated analysis or extended monitoring requiring more frequent or increased number of manual withdrawals of complex fluid samples poses other disadvantages to patient care; e.g., it increases the opportunity of air emboli or other unwanted substances to enter the body, consumes excessive volumes of precious body fluids, such as blood, and results in added expense for sampling supplies (disposable needles, syringes, collection tubes, reagents, etc.), technician time, and costly analyzing instruments.
Similar arguments teach against the use of off-line monitoring for industrial chemical process systems where any significant lag between the time a sample is withdrawn from a short-term or fast reacting process stream to when the sample is analyzed, would not afford the instantaneous assessment necessary in providing optimal control. Thus, time lags associated with off-line or in vitro analysis detract substantially from the use of this art when continuous or near-continuous analysis is desired and offer, at best, retrospective information.
The disadvantages and limitations associated with in vitro or off-line analysis have promoted considerable research toward the development of on-line sensing methods. For example, miniature sensors small enough to be used on or inside the body (e.g. intravascular) with the ability to continuously measure selected components in blood or other body fluids have been proposed based upon a wide variety of chemical transduction methods. These include sensing elements, such as, ion-selective electrodes (ISE) based upon potentiometric principles and more recently chemically sensitive field effect transistors (CHEMFETS) based upon microelectronic impedance-converting elements which are capable of measuring electrolytes, such as hydrogen, potassium, sodium, calcium and other ions. In addition, electroenzymatic based sensors utilizing polarographic principles, electrocatalytic sensing elements based upon direct catalytic oxidation, heat sensitive thermistor devices utilizing exothermic enzyme reactions, optical sensing elements utilizing fiber optic devices, CHEMFETS, ISFETS and other types of sensing elements have been proposed for the measurement of nonionic substances in complex fluids, such as dissolved gases (i.e.) oxygen, carbon dioxide), glucose and others.
The use of these proposed chemical sensors in the body is possible in a variety of ways, i.e., in vivo (transcutaneous, percutaneous, or implantable via subcutaneous, intravascular, intraperitoneal routes), and ex vivo (via extracorporeal circuits such as heart-lung bypass, kidney dialysis, hemoperfusion, apheresis and the like) modes, some of which allow access to the complete molecular spectrum of species in complex fluids in the body. In vivo and ex vivo chemical sensing modes hold the potential to continuously measure a wide variety of selected components in complex fluids, such as blood and the like, but have not overcome problems associated with the direct contact of the chemical sensor with the complex fluid. For example, major problems remain to be solved with long term implantable chemical sensors, including biocompatiblity problems with blood e.g. poisoning and/or fouling of the sensing components due to non-selective adsorption or precipitation, tissue encapsulation of the sensor, poor membrane selectivity and others all of which adversely affect sensor performance. Thus, in vivo implantable chemical sensors intended for continuous use are not yet satisfactory for routine patient care i.e. implantable chemical sensors would only be practical if they can remain stable for continuous and long term monitoring, and not require frequent recalibration due to sensor drift or replacement due to failure when exposed to complex fluids, such as blood. Furthermore, invasive chemical sensors employing sensitive electroactive materials or biologically labile components, such as an enzymes, are subject to deactivation when exposed to sterilization. Also, enzymes are known to perform suboptimally in complex fluids, such as, blood, where, in addition to the existence of antagonistic agents, limiting chemical reaction conditions exist which significantly reduce the activity or conversion capability of the enzyme. For example, it has been shown that when the enzyme glucose oxidase is employed to measure glucose in blood in vivo, the inherent limited oxygen environment in the body, where oxygen partial pressures are typically less than 100 mmHg, significantly reduces the activity level of the enzyme, thus restricting sensor performance in the absence of supplemental oxygen means. In view of the related problems associated with the direct contact of sensors with complex fluids, the packaging of sensors, i.e., design and location of the housing interfacing with the sensor, is critical for protection against environmental influences and is a major limiting factor in the design of biosensors. A more complete review of the current status and the limiting factors of chemical sensors can be found in I. Lauks, Symposium on Biosensors in Medicine, Medical Instrumentation, Vol. 19, No. 4., July-Aug, 1985; Engels et. al., Medical Application of Silicon Sensors, J. Phys. E: Sci: Instrum. Vol. 16. pages 987-994, 1983, and Potvin et. al., Proceedings of the Symposium on Biosensors, IEEE/NSF Symposium on Biosensors, Los Angeles, Sept. 15-17, 1984.
The present invention teaches the use of a filtration method and device for withdrawing, collecting and sensing chemical constituents from complex fluids and which overcomes many of the problems associated with continuous online sensing of complex fluids such as blood. It offers the capability of continuous measurement of dissolved species while selectively removing interfering substances prior to contacting the sensing element(s). It can be used in in vivo, implantable and percutaneous modes, as well as ex vivo with a wide variety of sensing elements. Its packaging offers a high degree of flexibility in the way and manner it interfaces with the sensing elements and the complex fluid, and in its ability to sense or measure species over a wide molecular spectrum simultaneously and without delay. It also allows the continuous collection of filtrate fractions of complex fluids which can be used, for example, for monitoring widely fluctuating body materials and for the measurement of substances existing at very low concentration levels. This contrasts with the prior art which generally teaches methods related to the chemical sensing of a relatively small number of only very low molecular weight species existing in complex fluids, such as, dissolved ions (eg. hydrogen, potassium), gases (eg. oxygen, carbon dioxide) and other relatively low molecular weight species (eg. glucose) and do not teach collection of filtrate fractions for chemical sensing. For example, use of the transcutaneous chemical sensing method is inherently limited to small diffusible gaseous substances, such as blood gases, which leave the complex fluid and permeate the underlying tissue and through the skin. Other proposed sensors which directly contact the complex fluid and utilize diffusive transport means to sense chemicals generally favor monitoring of low molecular weight, highly diffusible substances. Furthermore, the present invention does not require the use of anticoagulants as is generally required by the prior art that teaches percutaneous methods requiring whole blood withdrawal to measure components in the bloodstream.
Previous attempts to eliminate the necessity of withdrawing whole blood and the need for anticoagulants taught the use of a dialysis membrane barrier situated in a manner to isolate the sensor from directly contacting the complex fluid to prevent clotting, and more recently to improve selectivity, enhance sensor response, and/or reduce the exposure of sensing components to interfering substances (e.g. catalase, or peroxidase interference of glucose enzymatic chemical sensors). However, the use of diffusion limited membrane sensor devices, such as sensors utilizing dialysis membranes in a diffusive transport mode, restrict desirable sensor responses to only highly diffusible, low molecular weight species (e.g. blood gases, electrolytes, glucose) and suffer from the inherent inability to measure and collect larger molecular weight species in real time; and in addition, do not allow the simultaneous real time measurement and collection of both small and large molecular weight species coexisting in a complex fluid, independent of the capability of the sensing element(s) to measure larger molecular weight species while having an acceptable response time. This is because mass transport in a liquid medium based purely on diffusion with no convection in the same direction as the diffusion is a relatively slow random molecular process particularly as the solute molecular weight increases. Described by what are known as Fick's laws of diffusion, the diffusion flux, J, of solute i in its simplest form is given by the expression, J.sub.i =-AD (.DELTA.C.sub.i /.DELTA.X), where A is area across which diffusion occurs, D is the diffusion coefficient of solute i, C.sub.i is the concentration of solute i and X is the distance. If a membrane, such as used in a dialysis process, is interposed between two fluid compartments having one complex and one simple fluid, the diffusive transport of solute i from a complex fluid such as blood across a thin dialysis membrane into an aqueous solution W in general is generally described as J.sub.i =A {DH/1}(C.sub.B -C.sub.W), where the quantity DH in the square bracket is called the solute membrane permeability, 1 is the distance, and the quantity (C.sub.B -C.sub.W) is the concentration gradient of solute i that exist between the fluid compartments. As the diffusion coefficient decreases with increases in the molecular size or weight of the solute or analate, an inherent disadvantage of diffusion dependent membrane processes is that the solute membrane permeability, defined as the product of its solubility and diffusivity, decreases with increasing molecular weight. With typical dialysis membranes, this effect is significant having reductions of up to 50% or more in solute membrane permeability possible even with only modest increases in solute size. For example, permeability reductions of this magnitude as the solute size increased from 180 MW (glucose) to 1355 MW (vitamin B.sub.12) were reported by Collins et. al., The Journal of Physical Chemistry, Vol. 83, No. 17, pages 2294-2301, 1979. In addition, as the difference in concentration of the solute between the two fluid compartments decreases due to diffusion so does the diffusive transport rate (flux) of solute decrease. Thus, the concentration response of an analate permeating into a fluid compartment opposite a complex fluid and separated by a dialysis membrane would typically be asymptotic in nature independent of its size, small or large, as it approaches the actual value in the complex fluid resulting in a longer sensor response time.
Unlike diffusion, a solvent volume flow occurs in membrane filtration where the total volume flux, J.sub.v, is described by J.sub.v =L.sub.p. .DELTA.P where L.sub.p is the pressure filtration coefficient and also known as the solvent membrane permeability and .DELTA.P is the hydrostatic pressure gradient and also known as the transmembrane presure (TMP). Thus in contrast to diffusion, solute transport by filtration means is determined primarily by the solvent filtration rate which in turn depends upon the solvent membrane permeability and the TMP. In general as the TMP increases, the solvent flow and the solute transport rate increases and is esentially independent of the solute size up to solute sizes where the rejection characteristics of the membrane become a factor. The solute retention characteristic of a membrane barrier is described by the reflection coefficient which is related to the solute sieving coefficient SC. The sieving coefficient, defined as one minus the reflection coefficient, is the coefficient for convective transport through the membrane and indicates the magnitude of the capacity for convective transport of the solute, with the bulk flow of solvent, across the membrane. In general, sieving coefficients of approximately one are possible over a much wider molecular weight range with filtration type membranes, such as ultrafiltration and microporous membranes, than with diffusion membranes such as dialysis. Thus, for a solute having little or no rejection (R=0) or a sieving coefficient of approximately one (SC=1), the solute transport rate is essentially the same as the membrane solvent filtration rate which in general increases as the hydrostatic pressure gradient increases and the solute filtrate concentration is essentially immediately equal in concentration to its concentration in the bulk fluid.
The present invention is thus intended to measure the concentration of selected substances in complex fluids, such as, blood, peritoneal, interstitial, lymph, cerebrospinal, tear, and other body fluids for purposes of medical research, diagnosis and treatment; as well as, in complex fluids used in biochemical engineering and biotechnology, such as, fermentation broths and the like for purposes of maintaining optimal control of chemical process fluid systems. Its capability of continuous measurement of one or more selected substances, small and large, in complex fluids offers additional advantages of interest to the clinical and biotechnology communities.
A particularly useful application of the present invention is the continuous measurement of one or more selected substances existing in body fluids, such as, blood. Such substances include dissolved gases, electrolytes, trace elements, simple sugars, such as glucose and other carbohydrates, drugs, triglycerides, lipids such as cholesterol, amino acids, nucleic acids, hormones such as insulin, enzymes, antibodies, complement and other proteins or protein derivatives and other biochemicals which range in molecular weight from less than 100 daltons to in excess of 100,000 daltons and even up to 1,000,000 daltons or so.
In clinical medicine, the present invention can afford the continuous monitoring of patient blood chemistries in a manner not yet possible or available with current technology. For example, in short-term critical care patient management, fast and accurate measurements of substances in whole blood are needed. The needs in critical care, intensive care, and emergency care are quite specific and well defined. They include determination of blood gases, pH, electrolytes(K+, CA++, Na+), key metabolites (e.g., glucose, bilirubin, creatinine,), drugs of abuse (e.g., alcohol, cocaine, etc.), myocardial indicators including creatinine kinase-MD, lactate dehydrogenase, and determination of others is highly desirable. In long-term patient management the present invention can be used for continuous biosensing, in vivo, for the control of chronic disorders, such as, the metabolic disorder known as diabetes mellitus, as well as, for therapeutic drug monitoring, microbial substances, infectious disease detection, detection of cancer markers, monitoring of pregnancy and other hormone indicators, antigens and antibodies and their complexes which are characteristic of autoimmiune disease, for genetic probes, as well as, for ions, dissolved gases, key metabolites, such as urea, and others. In addition, with proper scaling the use of this invention for the on-line continuous monitoring of nutrients such as glucose is desirable in optimizing the product yield of genetically engineered substances from complex fluid mixtures used in chemical process biotechnology.
It is also apparent that the present invention can be used for monitoring local chemical events in the body. For example, it could be used to monitor the influence of a single organ on the composition of fluids by monitoring afferent and efferent blood vessels of body organs and the excreted and secreted products of these organs. The present invention can also be used to monitor the metabolic changes in an organ or the metabolic fate of substances such as drugs.
The prior art taught on-line or in vivo methods and apparati for the analysis of components in complex fluids over twenty-five years ago (see New York Academy of Sciences, Vol. 87 pp. 729-744, 1960), but they have experienced limited utility due to distinct disadvantages that these approaches fail to overcome when analyzing complex fluids, such as blood and the like. Furthermore, the prior art taught methods and apparati for the continuous measurement of substances in blood in vivo over twenty-five years ago, yet no practical and dependable device has come forth to meet this clear need; this attests to the unforeseen disadvantages and limitations that these devices suffer from and the clear need and advantages of the features offered by the present invention.
The disadvantage and limitations of cited teachings of the prior art will further illuminate more specifically the distinct advantages of the present invention. For example, it was as early as 1960 that Weller, et. al., and Ferrari et.al., Annals New York Academy of Sciences, Vol. 87, pages 658-669 and 729-745 respectively, (1960) and Kadish, Transactions of the American Society for Artificial Internal Organs, Volume 9, pages 363-367, (1963), disclosed an on-line continuous chemical analysis of blood glucose. However, these systems required the use of anticoagulants, such as heparin, utilized large, expensive and bulky equipment situated on a bench top located a distance from the patient, thereby requiring that excessive volumes of whole blood be pumped outside the body and discarde. In addition, these systems were able to measure only small molecular weight substances such as glucose, could not be used continuously for long-term monitoring purposes, had slow response times, and did not lend themselves to portability.
Another related disclosure, Coggeshall U.S. Pat. No. 3,785,772, teaches a device consisting of a pair of syringes which withdraw whole blood from a patient via venipucture, the addition of an anticoagulant to prevent blood clotting, a dialysis membrane to allow a diffusible species to be separated from the blood, a reactant which converts the diffusable species into a measurable reactant-blood constitutent complex and a sensor which can detect the concentration of the reactant-blood constitutent complex. However, the Coggeshall apparatus is also cumbersome, limited to intermittent analysis of only low molecular weight species, and requires excessive blood volumes for near continuous multiple sequential analysis. The reactant also needs replacement after each measurement as it forms an irreversible complex and is thus unable to sense instantaneous changes in the body.
Further improvements to these methods were made by the apparati of Clark et.al. in U.S. Pat. Nos. 3,838,682 and 3,910,256 which comprised an intermittent withdrawal and monitoring system for small molecular weight substances, i.e., blood gases, (0.sub.2, CO.sub.2) and pH. These patents disclose a system wherein whole blood is automatically and intermittently withdrawn from an arterial catheter and delivered to a fully automated blood gas analyzer measuring system for analysis and return to the patient. The main disadvantage of this system is its inherent limitation to intermittent withdrawal sampling frequency and analysis. Also, its excessive blood volume precludes continuous monitoring of blood constituents, and additional reagents and solutions are required to maintain sterility and patency of the catheter, A further disadvantage is its inability to measure other body fluid constitutents and its inherent nonambulatory nature.
These early attempts at the continuous measurements of constituents in whole blood were further improved upon by placement of various measuring devices in situ at various body locations either directly in contact with the complex fluid or separated by a diffusion controlled membrane barrier as a means of eliminating the necessity of removing whole blood from the patient. However, these disclosures in general were restricted to the measurement of only small molecular weight gaseous and liquid species, and did not easily lend themselves to continuous monitoring, and did not utilize convective filtration to obtain complex fluid fractions.
For example, Brumley, U.S. Pat. No. 3,123,066 taught the use of an optical catheter that could be inserted into a blood vessel and placed in direct contact with blood. However, this apparatus is inherently limited to selected optically sensitive species, such as oxygen, and did not teach methods to remove intefering substances. Rybak, U.S. Pat. No. 3,787,119 teaches the use of a multiple photometer for insertion directly into the bloodstream in direct contact with blood but is restricted to substances that can be detected by colorimetry and does not teach methods to remove intefering substances.
McKimley, U.S. Pat. No. 3,438,241 taught the use of a permeable membrane to selectively measure gases in gaseous and liquid mixtures. However, he did not teach the use of this apparatus for measurement of gaseous constitutents in the body and for non-gaseous constituents in complex fluids in vitro or in vivo.
Polanyi, U.S. Pat. No. 3,461,856 combined the optical catheter taught by Brumley with a gas permeable membrane similar to that of McKimley for measuring the oxygen saturation of blood transcutaneously. However, this method irestricted to blood gas parameter measurements only. Other, more recent art reciting transcutaneous gas sensing of body fluids including Delpy U.S. Pat. No. 4,220,158 and Vesterager et.al. U.S. Pat. No. 4,274,418, have similar disadvantages and limitations.
Other prior art teaching invasive percutaneous methods of detecting substances in body fluids, although having potential access to essentially the complete molecular spectrum of dissolved species in body fluids, were inherently restricted to the sensing of small molecular weight gaseous species.
This included, Gardner et. al., The Journal of Thoracic and Cardiovascular Surgery, Vol. 62, No. 6, pages 844-850 (1971), which discloses a percutaneous method and apparatus to measure blood gases consisting of a diffusion controlled, gas permeable Teflon-coated cannula, whereby blood gases diffuse from tissue through the hydrophobic membrane cannula and are shown by a vacuum applied to the proximal end of the cannula to a mass spectrometer. This method is limited to sensing low molecular weight gases not to mention the expense, size and limited utility of a dedicated mass spectrometer for on-line blood chemistry.
Also, Seilaff et al, U.S. Pat. Nos. 3,983,864 and 4,016,864, teach a method and apparatus comprising a gas permeable membrane probe containing a carrier gas which is inserted into a blood containing vessel in the body. A carrier gas such as helium is then allowed to come into equilibrium with the blood gas via blood gas diffusion across the membrane into the carrier gas. The carrier gas is then removed from the probe for in vitro analysis. This device is also limited to gas analysis and hence limited utility for complex body fluid analysis, as well as, the inherent disadvantages associated with pure diffusional equilibrium processes and subsequent in vitro analysis.
Kowarski, U.S. Pat. Nos. 4,006,743 and 4,008,717 teaches a portable microdiffusion chamber for collection of widely fluctuating body materials. However, this device has many disadvantages including the requirement of whole blood withdrawal, the addition of anticoagulant, and limitations of diffusional collection means. It also requires off-line sensing and thus is not amenable to the fast response times for continuous on-line measurement.
Brantigan, U.S. Pat. No. 4,016,863 also teaches a percutaneous apparatus for in vivo sampling of blood gases in tissue consisting of a gas permeable membrane tube containing a liquid which is allowed to equilibrate with tissue gases. However, this method is restricted to discrete sampling since the gas permeable probe containing the equilibrated fluid must be retrieved from the body before blood gas analysis can be performed and it is also restricted to a narrow range of blood chemistry measurements i.e., blood gases.
A similar approach was reported by Myer et al, Surgery, Vol. 71, No. 1, pages 15-21 (1972), and Niinikoski et al, Vol. 71, No. 1pages 22-26 (197672), in which both methods teach the utilization of a gas permeable silicone probe filled with saline serving as the equilibration liquid which is allowed to equilibrate with surrounding tissue gases that diffuse across the gas permeable membrane probe into the saline solution and which is removed from the stationary implanted permeable tube for in vitro anaylsis. The inherent disadvantages are again its limited utility to monitoring gases only, its diffusional limited sampling period, multiple incisions and its intermittent in vitro analytical methodology.
Goodwin et al, U.S. Pat. No. 4,340,615 made further improvements to in vivo gas sensing by teaching the use of multiple membrane layer gas sensing probe to reduce problems of gas-depletion and flow dependence and improve response time. However, this art does not teach the measurement of non-gaseous species in complex fluids.
Other prior art taught methods of in vivo sensing of selected non-gaseous species such as glucose in complex fluids, such as blood. For example, Kadish, U.S. Pat. No. 3,512,517 teaches the use of an indwelling intravenous catheter having a dialysis membrane to measure blood glucose, in vivo. However, this apparatus requires the use of an anticoagulant and is limited to only highly diffusible, low molecular weight substances, such as glucose and cannot withdraw complex fluid fractions from whole blood.
Guilbault et. al., U.S. Pat. No. 3,948,745 teach the use of an amperometric electrode sensor housing immobilized enzyme held in contact with the sensing portion of the electrode by means of a cellophane dialysis membrane for the measurement of glucose. Again, this art does not teach how to withdraw complex fluid fractions from complex fluids such as blood nor does it teach in vivo sensing means. It is also restricted to highly diffusible low molecular weight components and is not suitable in its present form for long term continuous monitoring with a non-easily interchangeable enzyme component. Similar factors also pertain to Newman, U.S. Pat. No. 3,979,274.
Clark et al U.S. Pat. No. 4,221,567, teaches a percutaneous method and apparatus for the measurement of blood constituents in vivo which involve a permeable hollow fiber liquid-filled, diffusion-controlled, membrane probe which allows blood constituents, i.e., blood gases, to diffuse into the liquid contained in the probe which, after equilibration, is transported to sensors which are self-calibrating. The main disadvantages of this teaching are the inability to withdraw complex fluid fractions and sampling frequency limitations associated with diffusional processes, particularly as the molecular weight of the analate increases.
Merrill, U.S. Pat. No. 3,638,639, teaches a percutaneous apparatus for monitoring lipid-soluble blood constituents. Merrill discloses a system consisting of a catheter containing a membrane and a lipid solvent in which only lipids are allowed to cross the membrane by dissolution in the membrane whereupon they are dissolved in a lipid solvent and transported out of the body through a catheter for analysis. The major disadvantage of this art is its restriction to sensing only lipids.
Shimada et. al., U.S. Pat. No. 4,273,636 teaches a CHEMFET based sensor having a semipermeable membrane containing a light darkening dye or pigment. However, neither in vivo sensing nor withdrawal of complex fluid fractions by bulk convective filtration are taught. Also, a sensing means that directly contacts a membrane barrier would, for in vivo measurement, generally require implantation of both the sensing element and the membrane and thus restrict its utility.
Nylen et. al., U.S. Pat. No. 4,311,789 teaches the use of an extracorporeal dialyzer membrane means for measuring low molecular weight constituents in complex fluids such as glucose in blood. The main disadvantages are the complexity, size and nonportable nature of this apparatus, the fact that its diffusional transport basis restricts response times of higher molecular weight species, and its inability to sense in vivo.
Another percutaneous method and apparatus for the measurement of blood constituents in vivo is described by Schultz, U.S. Pat. No. 4,344,438 which teaches a dialysis membrane probe filled with a liquid containing receptor sites and competing ligands which cannot diffuse out of the permeable probe due to their large molecular weight and connected to a light carrying chamber in contact with a light source and detector. As selected plasma constituents diffuse across the permeable dialysis membrane, receptor site-competing ligand complexes are reversibly formed which affect the intensity of light emitted or absorbed in a way that is proportional to the concentration of the selected plasma constituents. The distinct disadvantages of this patent are the sampling frequency associated with diffusional and binding processes, the inability to withdraw and collect complex fluid fractions, the limitation on the number of constituents to be analyzed due to the finite number of specific binding agents and ligands contained in this implantable probe, and the requirement of an expensive and bulky fiber optic light source and detector.
Johnson, U.S. Pat. No. 4,356,074, teaches the use of a multilayer enzyme membrane sensor system to selectively exclude passage of high molecular weight interfering substances with one layer and other interfering low molecular weight substances with another membrane layer. However, this art does not teach methods of collection and sensing in vivo and relies upon diffusive transport of selected materials to the sensing element.
Suzuki et. al. U.S. Pat. No. 4,388,166 concerns an electrochemical measuring apparatus employing an enzyme electrode. The electrode is equipped with a filter membrane, an enzyme electrode, and an asymmetric semipermeable membrane over the immobilized enzyme membrane. The asymmetric semipermeable membrane in contact with a liquid with an organic ingredient to be measured, e.g. blood, serves to permit an ingredient such as glucose to contact the enzyme membrane while preventing contact with high molecular weight material which would contaminate the electrode. However, the patent does not utilize a bulk convective filtration means to transport the ingredient to the sensor but rather relies solely on diffusional transport of the ingredient through the asymmetric membrane barrier. Further, its use in this application is indicated to be not entirely understood but is suggested to suppress irregular diffusion and noise which interferes with the electrochemical apparatus of this art. It is also not concerned with procedures for in vivo sampling of body fluid components and does not utilize hollow fiber membranes.
D'Orazio et al, U.S. Pat. No, 4,415,666 teaches an enzyme electrode membrane apparatus in which the membrane has a thick porous layer dispersed with enzyme and a thin layer having a desired molecular weight cutoff of approximately 300 daltons. In its described form, this apparatus is limited to diffusional transport of selected species. It also does not teach bulk convective filtration means for collection and sensing and is not concerned with procedures for in vivo sampling of body fluid components and does not utilize hollow fiber membranes.
Bessman, et. al, U.S. Pat. No, 4,431,004 teaches a method and apparatus to account for oxygen limiting conditions that in general exist in glucose/glucose oxidase based sensors. This are teaches the use of a double electrode system whereby one electrode senses the absolute oxygen concentration. However, this art does not teach the use of a gas permeable membrane device to eliminate oxygen limiting conditions as is taught in the present invention.
Margules, U.S. Pat. No. 4,432,366 teaches a reference electrode catheter for in vivo sensing having a hydrogel membrane which forms an ion diffusion barrier between body fluids and sensor electrolyte material. The major limitation of this device is its sensing of only very small ionic species and it does not teach a bulk convective filtration means.
Cerami, et. al. U.S. Pat. No, 4,436,094 teaches a method wherein the sensor utilizes a semipermeable membrane probe containing a complexing agent that causes a change in the electronic activity of the sensor matrix rather than causing a change in the light emitted or absorbed. Specifically, the sensor is comprised of a semipermeable membrane housing an electrical charge transfer medium comprising a reversible complex of a binding macromolecular component and a charge bearing carbohydrate component, said membrane being permeable to glucose and other small molecular weight species and impermeable to the carbohydrate and macromolecular components. As glucose, present in the body fluid, diffuses across the membrane into the sensor fluid matrix, it displaces the charged carbohydrate with the result that the charged carbohydrate components enter the electric field and cause a change in the magnitude of electrical charge. Some of the disadvantages are similar to those of Schultz, and the procedure does not use an asymmetric hollow fiber ultrafiltration membrane to obtain complex fluid fractions as utilized in this present invention.
Other membrane sensor devices include Wilkens, U.S. Pat. No. 4,440,175 who teaches a membrane electrode for in vivo sensing of a non-ionic species such as glucose in which anion exchange material and a water-insoluble salt of the non-ionic species is dispersed in the membrane matrix; Peterson et. al., U.S. Pat. No. 4,476,870 who teaches a fiber optic oxygen in vivo gas sensing probe containing a hydrophobic gas permeable membrane envelope housing a fluorescent dye; Gough, U.S. Pat. No. 4,484,987, who teaches a sandwich-type membrane apparatus comprising both hydrophobic and hydrophilic membrane materials; Rogoff, U.S. Pat. No. 4,538,616 who teaches an implantable osmotic sensing membrane transducer for in vivo sensing of glucose; Lubbers, et. al, U.S. Pat. No. RE. 31,879 who teaches a fiber optic membrane probe for sensing gases in vivo, and Higgins, et. al., U.S. Pat. No. 4,545,382 who teach a ferrocine mediated enzyme sensor probe; and all of which fail to teach bulk convective filtration means for collecting filtrate fractions and sensing selected components in filtrate fractions obtained from complex fluid media.